The effect of thymosin fraction 5 on the mixed lymphocyte response (MLR) of peripheral blood lymphocytes (PBL) of aging normal and autoimmune individuals was studied. There was little effect of age (20-86 years of age) on the MLR response of normal individuals. Thymosin Fr. 5 (100 micron g/ml) consistently elevated the response 15-35 percent in all age groups when cultured with the lymphocytes. In two series of experiments, the greatest effect of thymosin on the elevation of the MLR was in the 40-59 age group. The effect of thymosin was dose dependent; a 3x greater elevation was observed when PBL were cultured with thymosin at 200 micron g/ml. The only exception to these effects of thymosin were in a group of PBL with unusually high MLR responses (40,000-80,000 CPM). Every individual whose cells responded in this range showed a dose dependent suppression of the MLR when cultured with thymosin. Two groups of autoimmune patients, diagnosed with either systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) were studied. The SLE group's (aged 17-33) cells showed a similar MLR response to that of the age matched controls, and no elevation of the response when cultured with thymosin Fr. 5. In contrast, the RA group's (aged 53-71) cells showed a deficient MLR, which was markedly enhanced by culture with thymosin Fr. 5(100 micron g/ml) (+108 percent) to normal levels seen with age, matched controls. A reduced effect was seen with higher doses of thymosin Fr. 5. (200 micron g/ml).